Recent studies have shown that calcium sequestration by mitochondria is intimately linked to the activity of pyruvate dehydrogenase (PDH); this observation coupled with the discovery of low-threshold calcium activated proteolytic enxymes in certain brain regions has led to the hypothesis that some cases of neuronal degeneration are caused by a disturbance of the intricate regulation of the PDH complex. Two lines of evidence have now appeared which may be pertinent ot his idea: 1) the severe dendritic atrophy seen in denervated hippocampus is preceded by a marked and selective depression of pyruvate flux through PDH as well as of pyruvate-supported calcium uptake and 2) PDH activity is selectively and dramatically decreased in samples of brain tissue from patients suffering from Alzheimer's disease. Taken together, these results suggest that the development of techniques for manipulating PDH activity in brain regions in which it is depressed may have important values in clinical and experimental studies. The proposed work is intended to develop such techniques and has the following goals: 1) establish how hippocampal denervation depresses PDH activity and calcium transport, 2) reproduce some of the salient features of Alzheimer's pathology in a cholinergic nucleus of the rat septum, 3) elevate PDH activity and calcium transport in regions in which they are depressed by systemic and/or central administration of drugs directed at he PDH regulatory protein, namely its Alpha-subunit phosphoprotein, and 4) measure the effects of PDH manipulation on neuropathology.